Acute Respiratory Distress Syndrome (ARDS) is an all-too-common form of severe lung injury that is triggered by a variety of factors including infectious, non-infectious and other damaging events. ARDS is a multi-factorial disorder in which inflammation and tissue fibrosis is the leading cause of morbidity and mortality. It is a plural symptom disorder that affects up to 200,000 patients annually in the US. Although supportive therapy has improved survival somewhat, there are no effective therapeutic agents for improving clinical outcome of patients with ARDS. In particular, glucocorticoids are not effective in treating this disorder. Therefore, there is an urgent need for the development of treatments to halt the progression of ARDS. ARDS in humans has several characteristic features, exemplified by diffuse alveolar damage (DAD), neutrophil and macrophage infiltration, fibrosing alveolitis, and lack of responsiveness to glucocorticoids. We have developed a small animal model of infectious-induced ARDS that displays many of the characteristics of human ARDS: (I) Histologically, our ARDS model exhibits DAD, hyaline membranes, hemorrhage due to vascular leakage, and disruption of alveolar epithelium;(II) Infiltrates composed primarily of neutrophils and macrophages;(III) The chronic phase demonstrates fibrosing alveolitis;(IV) Treatment with glucocorticoids does not lead to significant modulation of the disease process;(V) A role for apoptosis involving the Fas/FasL pathway has been suggested in our infectious model of ARDS. Thus, this model provides a very relevant model for infection-induced ARDS and for deciphering the mechanism of action of the potent anti-oxidant, anti-microbial, anti-inflammatory agent, curcumin. We hypothesize that the ingestion on a regular basis of curcumin the major component of the Indian spice turmeric, modulates cellular infiltration, proinflammatory cytokine expression, and signal transduction pathways in the lungs, leading to resistance against infectious-induced ARDS. Our preliminary data suggest that treatment with curcumin inhibits DAD and fibrotic lesion development in reovirus 1/L-induced ARDS. Our specific aims will elucidate the mechanisms of action of curcumin focusing on the inflammatory infiltrate, the release of cytokines, apoptosis, and the signal transduction pathways activated and modulated by curcumin. Elucidating the underlying mechanisms of action of potential CAM therapies such as curcumin will facilitate their integration into conventional medical care. 1. Aim #1 will test the hypothesis that curcumin significantly improves ARDS survival and inhibits development of DAD and fibrosis by modulating the inflammatory infiltrate and expression of key cytokines/chemokines including G- &G/M-CSF, IFN3, MCP-1, MIP-2, and MIP-11. 2. Aim #2 will test the hypothesis that curcumin modulates signaling pathways involved in ARDS, which includes pathways mediated by PKC, Caveolin-1, ERK/MEK, NFkB, TGF2, and apoptotic pathways. PUBLIC HEALTH RELEVANCE: The central goals of these experiments are to investigate the molecular mechanism through which curcumin, a potential CAM therapeutic, protects against infectious ARDS. Although supportive therapy has improved survival somewhat in human ARDS patients, there are no effective therapeutic agents for improving clinical outcome of patients with ARDS. Therefore, there is an urgent need for the development of treatments to halt the progression of ARDS. Elucidating the underlying mechanisms of action of potential CAM therapies will facilitate their integration into conventional medical care. In addition, mechanistic studies of CAM therapies will improve the identification of key study endpoints, and thus, strengthen the design of CAM clinical trials.